Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000551708 | SCV000627693 | uncertain significance | Long QT syndrome | 2024-06-18 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 3294 of the ANK2 protein (p.Asn3294His). This variant is present in population databases (rs763211298, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 457073). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV000619323 | SCV000737768 | benign | Cardiovascular phenotype | 2024-03-12 | criteria provided, single submitter | clinical testing | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786099 | SCV000924740 | uncertain significance | not provided | 2017-07-24 | no assertion criteria provided | provider interpretation | p.Asn3294His (N3294H; c.9880A>C) in exon 38 of the ANK2 gene (NM_001148.4) Chromosome location 4:114279654 A / C We classify this as a Variant of Uncertain Significance (VUS), probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not been reported in the literature in association with disease. It is present in population databases at a higher frequency than would be expected for a pathogenic variant (PMID: 28166811), and specifically in individuals with Latino ancestry like our patient. This suggests that it may be a benign, ethnicity-specific variant. Of note: our patient also has another variant that is Likely Pathogenic and explains his phenotype (sick sinus syndrome). This is a nonconservative amino acid change, resulting in the replacement of a polar asparagine with a positively-charged histidine. The asparagine at this location is poorly conserved across ~100 vertebrate species for which we have data. Of note: the histidine amino acid residue is found in more than one mammalian species, suggesting that this missense change does not adversely affect protein function. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 23 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 22 individuals with Latino ancestry (for the highest allele frequency: 0.066%), and 1 person with “Other†ancestry. Our patient’s ancestry is Latino. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. |